The rupture of unstable atherosclerotic plaque is the most frequent event leading to thrombus mediated ischemic cardiovascular disease, which remains the leading cause of mortality in industrialized societies. The processes leading to plaque vulnerability are multi-factorial, and it is widely conceived that an intricate interplay between biomechanical, compositional and morphological determinants of atherosclerosis influences plaque stability. The development of novel intracoronary imaging techniques that provide composite information about these factors is vital for identifying rupture-prone atherosclerotic plaques, guiding therapy, and for providing insights regarding plaque stabilization in patients. We recently showed that Laser Speckle Imaging (LSI), a new optical technique which measures the Brownian motion of endogenous particles in tissue, is highly sensitive for evaluating plaque viscoelasticity, composition and structure. Our prior work, conducted on cadaveric arterial specimens demonstrated that LSI has high accuracy for diagnosing atherosclerotic plaque type, measuring collagen content, and necrotic core area, and determining fibrous cap thickness. The goal of the current proposal is to develop an LSI system and catheter for in vivo intracoronary use. We envision that this work will potentially yield a single platform to evaluate coronary plaque biomechanics, composition and structure in patients. The Aims of this proposal are motivated by our prior experience in investigating the diagnostic potential of LSI and the expertise of our laboratory in fabricating miniature optical catheters for human use. Although we have demonstrated the principles of LSI ex vivo, the development of an intracoronary LSI catheter and system capable of imaging long coronary segments in vivo presents considerable technical challenges. In Aim 1 of this research we will focus on overcoming these challenges by developing LSI instrumentation and an intracoronary catheter capable of evaluating coronary vasculature in the presence of blood flow and cardiac motion. The diagnostic accuracy of LSI in identifying plaque type and characterizing structural features will be determined using ex vivo arterial tissue and phantom studies. In Aim 2 of this work we will demonstrate the feasibility of intracoronary LSI using a human to swine coronary xenograft living animal model to permit evaluation of human atherosclerotic plaques under in vivo physiological conditions. With the successful culmination of the aims of this proposal, we will have developed a novel intracoronary LSI technique and validated critical milestones in its path to clinical applicability.Narrative Acute coronary syndromes frequently result from the rupture of unstable coronary plaque. Intracoronary Laser Speckle Imaging will potentially provide a unique method to evaluate multiple determinants of plaque stability and facilitate the detection of high-risk coronary plaques in patients.